METABOLIC DISEASES: NIEMANNPICK DISEASE, VON GIERKE DISEASE, AND GALACTOSEMIA
|SELECTED METABOLIC DISEASES WITH SKIN FINDINGS|
There are a plethora of metabolic diseases that can have various cutaneous skin findings. These conditions, on the whole, are uncommon and are rarely encountered by the practitioner except in a tertiary referral center. However, knowledge of these uncommon diseases is important, because prompt recognition and diagnosis can lead to proper referrals and a better outcome for all involved. Three such metabolic disorders are Niemann-Pick disease, von Gierke disease, and galactosemia.
Niemann-Pick disease is a heterogenous group of conditions resulting from inability to properly metabolize sphingomyelin. There are three clinical variants, which have been designated types A, B, and C. They are all inherited in an autosomal recessive pattern, with the highest prevalence in people of Ashkenazi Jewish descent. Most cases are fatal in early childhood. Mental delay is profound. The disease results in massive hepatosplenomegaly caused by the excessive accumulation of sphingomyelin in various tissues. Niemann-Pick disease is caused by an abnormal lysosomal lipid enzyme degradation system, and it is therefore considered to be a lysosomal storage disease. Sphingomyelin is degraded into ceramide by the action of the enzyme sphingomyelinase. Type A and type B disease are similar in that the ASM gene, which encodes the acid sphingomyelinase enzyme, is mutated. This mutation leads to an inability of the lysosomes to metabolize sphingomyelin. Sphingomyelin accumulates in the liver and spleen. Severe neurological disorders occur in type A disease, but not in type B, and this is the only factor differentiating the two. Patients present in infancy or early child-hood. Skin findings include xanthomas and a waxy skin surface. Retinal examination reveals a cherry-red spot on the fovea. Niemann-Pick type C disease, which is caused by a mutation in the NPC1 or the NPC2 gene, does not involve any cutaneous findings. The cells are unable to normally process endocytosed cholesterol. Treatments are limited, with stem cell transplantation having been used with some efficacy. von Gierke disease, also known as glycogen storage disease type I, can be subdivided into types Ia and Ib. These autosomal recessive diseases are caused, respectively, by defects in the enzymes glucose-6-phosphatase and glucose-6-phosphatase translocase. These defects prevent normal gluconeogenesis from glycogen stores. Patients develop profound hypoglycemia during periods of fasting because they are unable to break down glucose-6-phosphate into glucose within the liver. This leads to a fatty liver and increased glycogen storage. Glucose-6-phosphate is shunted into glycolysis, which results in increased lactate production.
Cutaneous findings in von Gierke disease include extensor xanthomas on the knees and elbows. Patients have a peculiar facies that has been described as a “doll-like face.” This has been shown to be caused by an increased amount of fatty tissue deposited in the cheeks. Patients have frequent nose bleeds and severe gingivitis along with oral ulcerations. During periods of hypoglycemia, cyanosis may be very noticeable, and it may lead eventually to hypoxic brain injury. These patients are also at higher risk for skin infections due to an abnormal neutrophilic response to gram-positive bacteria. Treatment is based on a diet of 60% to 70% carbohydrates to avoid episodes of hypoglycemia.
Galactosemia is a rare autosomal recessive disorder that results from a defect in the enzyme galactose-1- phosphate uridyltransferase. It is caused by a mutation of the GALT gene on the short arm of chromosome 9. This mutation results in an increase of galactose-1- phosphate in various tissues. Nervous tissue, the lens, and the liver are areas of massive accumulation. This leads to the sequelae of the disease, predominantly mental delay, cataracts, and liver disease. The main cutaneous findings are jaundice secondary to liver disease and cutaneous signs of coagulopathy such as petechiae and hemorrhage. Cataracts are a well-known sign of galactosemia and are directly caused by the accumulation of galactitol in the lens, which results in edema and eventual cataract formation. Therapy requires he strict avoidance of galactose and lactose in the diet.